Morphine or other bimodally-acting opioid agonists are administered to relieve severe pain due to the fact that they have analgesic effects mediated by their activation of inhibitory opioid receptors on nociceptive neurons (see North, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81 (1990)). However, bimodally-acting opioid agonists also activate opioid excitatory receptors on nociceptive neurons, which attenuates the analgesic potency of the opioids and results in the development of physical dependence thereon and increased tolerance thereto (see Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)), as well as hyperexcitability, hyperalgesia and other undesirable (excitatory) side effects. As a result, a long-standing need has existed to develop a method of both enhancing the analgesic (inhibitory) effects of bimodally-acting opioid agonists and limiting the undesirable (excitatory) side effects caused by such opioid agonists.
The grandparent Patent Application for the instant invention, Ser. No. 07/947,690, relates to a specific group of opioid agonists for use as low/non-addictive analgesics and for the treatment of opioid addiction. In the grandparent Application, it is stated that this group of opioid agonists bind to and activate inhibitory but not excitatory opioid receptors. In contrast, morphine and most other opioid alkaloids and peptides elicit bimodal effects by binding to and activating both excitatory and inhibitory opioid receptors.
To date, no method has been discovered or developed whereby two opioid compounds are co-administered, one of which binds to and acts as a selective agonist at inhibitory opioid receptors to cause analgesia and the other of which binds to and acts as a selective antagonist at excitatory opioid receptors so as to attenuate undesirable side effects caused by the administration of bimodally-acting opioid agonists while simultaneously enhancing the analgesic effects of said bimodally-acting opioid agonists.
It is therefore an object of this invention to provide a method of enhancing the analgesic potency of morphine and other bimodally-acting opioid agonists by blocking their anti-analgesic side effects.
It is a further object of this invention to provide a method of attenuating physical dependence, tolerance, hyperexcitability, hyperalgesia and other undesirable side effects caused by the chronic administration of bimodally-acting opioid agonists.
It is another object of this invention to provide a method for maintenance treatment of previously detoxified opiate, cocaine and alcohol addicts utilizing ultra-low doses of an excitatory opioid receptor antagonists, either alone or in combination with long-term administration of low doses of methadone.
It is yet another object of this invention to provide a composition which enhances the analgesic effects of bimodally-acting opioid agonists while simultaneously attenuating undesirable side effects caused by said opioid agonists, including physical dependence, tolerance, hyperexcitability and hyperalgesia.
It is still a further object of this invention to provide a composition which is useful for treatment of opiate, cocaine and alcohol addicts.